Background: The epidermal growth factor receptor (EGFR) signaling pathway
plays a key role in regulation of cellular growth and development. While highly
studied, it is still not fully understood how the signal is orchestrated. One of
the reasons for the complexity of this pathway is the extensive network of
inter-connected components involved in the signaling. In the aim of identifying
critical mechanisms controlling signal transduction we have performed extensive
analysis of an executable model of the EGFR pathway using the stochastic
pi-calculus as a modeling language.
Results: Our analysis, done through simulation of various perturbations, suggests
that the EGFR pathway contains regions of functional redundancy in the upstream
parts; in the event of low EGF stimulus or partial system failure, this
redundancy helps to maintain functional robustness. Downstream parts, like the
parts controlling Ras and ERK, have fewer redundancies, and more than 50{\%}
inhibition of specific reactions in those parts greatly attenuates signal
response. In addition, we suggest an abstract model that captures the main
control mechanisms in the pathway. Simulation of this abstract model suggests
that without redundancies in the upstream modules, signal transduction through
the entire pathway could be attenuated. In terms of specific control mechanisms,
we have identified positive feedback loops whose role is to prolong the active
state of key components (e.g., MEK-PP, Ras-GTP), and negative feedback loops that
help promote signal adaptation and stabilization.
Conclusions: The insights gained from simulating this executable model facilitate
the formulation of specific hypotheses regarding the control mechanisms of the
EGFR signaling, and further substantiate the benefit to construct abstract
executable models of large complex biological networks.